Copyright © 2005, European Society of Cardiology
Tumor necrosis factor-
promotes atherosclerotic lesion progression in APOE*3-leiden transgenic mice
aDepartment of General Internal Medicine, Leiden University Medical Center, The Netherlands
bDepartment of Cardiology, Leiden University Medical Center, The Netherlands
cDepartment of Hematology, Leiden University Medical Center, The Netherlands
dTNO-PG/Gaubius Laboratory, Leiden, The Netherlands
eDepartment of Molecular Genetics, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands
fDepartment of Pathology, Maastricht University, Maastricht, The Netherlands
* Corresponding author. Department of General Internal Medicine, Leiden University Medical Center c/o TNO Prevention and Health, Gaubius Laboratory, Zernikedreef 9, P.O. Box 2215, 2301 CE Leiden, The Netherlands. Tel.: +31 71 5181421; fax: +31 71 5181904. Email address: lsm.boesten{at}pg.tno.nl
Objective: Tumor necrosis factor-
(TNF) is a pleiotropic cytokine exerting both inflammatory and cell death modulatory activity, and is thought to play a role in the pathogenesis of atherosclerosis. Studies in mice indicated that TNF affects atherosclerosis minimally or not under conditions that allow fatty streak formation. Here, we examined the possible role of TNF in advanced and complex atherosclerotic lesions.
Methods and results: To induce atherosclerosis, TNF-deficient (Tnf–/–) APOE*3-Leiden and control APOE*3-Leiden only mice were fed a cholesterol-rich diet. Comparable levels of plasma cholesterol and triglycerides and the systemic inflammatory parameters, serum amyloid A and soluble intercellular adhesion molecule-1 were found in APOE*3-LeidenTnf–/– and control mice. Although absence of TNF did not affect the quantitative area of atherosclerosis, APOE*3-LeidenTnf–/– mice had a higher relative number of early lesions (46.1% vs. 21.4%) and a lower relative number of advanced lesions (53.9% vs. 78.6%, P=0.04). In addition, the advanced lesions in APOE*3-LeidenTnf–/– mice showed less necrosis (9.9 ± 12.1% vs. 23.4 ± 19.3% of total lesion area, P=0.04) and an increase in apoptosis (1.5 ± 1.5% vs. 0.4 ± 0.6% of total nuclei, P=0.03).
Conclusions: Our data indicate that TNF stimulates the formation of lesions towards an advanced phenotype, with more lesion necrosis and a lower incidence of apoptosis.
KEYWORDS Atherosclerosis; Cytokines; Apoptosis; Necrosis; Transgenic animal models
Time for primary review 28 days
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